Acids of the cyclopentano polyhydro phenanthrene series and their derivatives and a method of producing the same



Patented Sept. 2, 1941" ACIDS or run cYcLorENrAno ronmnao PHENANTHRENEseams AND mm RIVATIVES AND A METHOD d7 PRODUC- INGTHESAME Hans-GeorgAllardt, Phillppsthal, and Lothar Strassberger,

Berlin-Wilmersd assignors, by mesne assignments, to ScheringCorporation, Bloomfield, N. J., a corporation'or Newv Jersey No Drawing.Application October 20, 1936, Serial No. 106,564. In Germany October 24,1935 31 Claims. (Cl. 260-397.!)

This invention relates .to acids of the cyclopentano polyhydrophenanthrene seriw and their derivatives, particularly to hydroxy acidsand unsaturated acids 01' the cyclopentano polyhydro phenanthrene seriesand their derivatives, and a method of producing the same.

It is known that ketones of the hydroaromatic series such ascyclohexanone or cyclopentanone can be converted with halogen aliphaticacid esters in the presence of metals, suitably zinc or magnesium, intothe corresponding hydro-aromatic hydroxy aliphatic acid esters; thesehydroxy aliphatic acid esters, on saponification with alkaline agentsyield the free hydroaromatic hydroxy aliphatic acids, on saponiflcationwith acid agents, however, by splitting of water under suitable reactionconditions the corresponding exoor endocyclic unsaturated hydro aromaticaliphatic acids can be obtained.

In accordance with the present invention, this reaction, known as theReformatzky reaction, can also be applied to ketones oi the cyclopentanop lyhydro phenanthrene series whereby hitherto unknown valuablecompounds are obtained.

To the ketones of the cyclopentano polyhydro phenanthrene series whichmay serve as starting materials for the process of the present inventionbelong a number oi. ketones with hormonelike actions such as thefollicle hormone of the formula CmHnOz, the male sex hormoneandrosterone of the formula CmHaoOa, and other similar substancesincluding androstenolone, cholestenone and so on and derivatives thereofwherein the hydroxyl group is replaced by a group convertible into thehydroxyl group.

The reaction 01' the halogen aliphatic acid esters on the ketones of thecyclopentano poly- Jhydro phenanthrene series in the presence oi metalssuitably zinc ormagnesium may take place in the usual manner as it isdescribed, for instance, in Houben-Weyl, Methods of the OrganicChemistry, vol. 3, 3d edition, Leipzi 1930, page 96 seq. and 897 seq.The hydrolysis of the esters of the acids formed may likewise be carriedout in the manner customary for hydrolysing an ester as it is described,for instance, in Houben-Weyl, Methods of the Organic Chemistry, vol. 2,3d edition, Leipzig 1930, page 6'17 seq.

The acids of the cyclopentano polyhydro phenanthrene series or theirderivatives obtained by the process of the present invention, 1. e. thecyclopentano polyhydro phenanthreno hydroxy acids or the correspondingunsaturated cyclopentano polyhydro phenanthreno acids or theirderivatives are valuable products as they are either themselvesphysiologically active or can be transformed into physiologically activesubstances; moreover the acids bbtained by the process of the presentinvention have the particular advantage of being more or less watersoluble. The following examples serve to illustrate the presentinvention without, however, limiting the same to them.

' Example 1 phuric acid, the benzene layer is separated,-

washed with sodium carbonate solution and dried. On careful evaporationof the benzene solution the ester of the 3,17 dihydroxy androstenyll7"-acetic acid is obtained which on alkaline saponiflcation accordingto customary methods yields the free acid, crystallising from alcohol incolorless needles of M. P. 220 with decomposition.

Example 2 In a similar manner to that of Example 1, 3.3 parts 01androstenolone-acetate-3 are treated in dry benzene with 3.7 parts of-bromo propionic-acid-ethyl-ester with the addition of 0.7 part of zincwool; on working up the ester of the 3,17 dihydroxy androstenyl 17"propionic acid is obtained and by alkaline saponification the free acidof M. P. 230 with decomposition.

Oi course, various modifications in the procedure oi the process of thepresent invention may be resorted to within the scope of the appendedclaims without departing from the principles set forth herein. Thus, forinstance, instead of the halogen aliphatic acid esters mentioned alsoother halogen aliphatic acid esters may be used for reacting with theketones got the cyclopentano polyhydro phenanthrene series.

What we claim is: 1. In a method oi producing acids of the vcyclopentanopolyhydro phenanthrene series and their derivatives, the step whichcomprises reacting a 13-methyl cyclopentano' polyhydrophenanthrenehaving aketo group in one of the '3 and 17 positions with ahalogen-substituted lower valiphatic monocarboxylic acid ester in thepresence of a metal capable of taking part in a Reiormatzky type 01'reaction.

2. A method according to claim 1, wherein the condensing reaction takesplace in the presence of a metal of the second group of the periodicsystem.

3. A method according to claim 1. wherein hydrolysis of the acid estersformed is carried out with an alkaline agent.

' 17-keto compound is employed as starting material which has in the3-position a substituent which on hydrolysis can be replaced by an OHgroup.

8. A method of producing acids of the cyclopentano polyhydrophenanthrene series and their derivatives, comprising reacting a 13-methyl cyclopentano polyhydrophenanthrene having a keto group in one ofthe 3 and 17 positions with a halogen-propionic acid ester in thepresence of a metal capablevof taking part in a Reformatzky type ofreaction.

9. A method of producing acids of the cyclopentano polyhydrophenanthrene series and their derivatives. comprising reacting a 13-methyl cyclopentano polyhydro phenanthrene having a keto group in one ofthe, 3 and 17 positions, with a bromo-propionic acid ester in thepresence of a metal capable of taking part in a Reformatzky type ofreaction.

10. A method according to claim 8, wherein the cyclopenta'no polyhydrophenanthrene compound is androstenol-3-one-17.

11. A method according to claim 8, wherein the cyclopentano polyhydrophenanthrene compound is a 17-keto compound having a substituent in the3-position which on hydrolysis can be replaced by an OH group.

12. 3,17'-dihydroxy-androstenyl-17" propionic acid oi. M. P. 220.

13. A neutralization reaction product of 3,17- dihydroxy-androstenyl-H"propionic acid.

14. An ester of 3,17' dihydroxy-androstenyl- 17" propionic acid.

15. A salt of It,17'-dil: ydroxy-androstenyl-17'' propionic acid. 7

16. The product of the oondensation'of a compound of the 13-methyl and10,13-dimethyl cyclopentano polyhydro phenanthrene series having a ketogroup occupying one of the 3 and 17 positions, with ahalogen-substituted loweraliphatic mono-carboxylic acid ester.

17. The unsaturated product of the condensation or a compoundor the13-methyl and 10,13-

series having a keto group occupy n one 0! the 3 and 17 positions, witha halogen-substituted lower aliphatic mono-carboxylic acid ester withelimination of the elements of water.

18. A compound oi the nuclearly saturated and nuclearly unsaturatedcyclopentano polyhydro phenanthrene series of the structure wherein Rindicates the radical Cams, n beins a whole number, R is a member of thegroup CHI n'ooca wherein R indicates the radical CIHII, n being a wholenumber, R. is a member of the group consisting of H, alkali metals andhydrocarbon radicals, x is a member of the group consisting of OH andradicals which are replaced on hydrolysis by an OH group, and Y is amember '01 the group consisting of H and CH3.

20. Acids of Iii-methyl cyclopentano polyhydro phenanthrenes having agroup in one of the 3 and 17-positions, R being a lower monocarboxylicaliphatic acid radical and n a whole number.

21. The neutralization reaction the acids defined in claim 20.

22. The esters of the acids defined in claim 20. 23. The salts of theacids defined in "claim 20. 24. A method accordingto claim 1 includingthe step of hydrolyzing the acid ester formed. 25. A method according toclaim,8 including the step 01' hydrolyzing the acid ester formed. 26. Amethod according to claim 9 including the step of hydrolyzing the acidester formed. 27. The method of producing acids or the 10,13-dimethylcyclopentano polyhydro phenanthrene series and their derivatives,comprising reacting a member of the group consisting voi androstenolonesand androstenolone derivatives products of wherein the hydroxy group hasbeenreplaced' I hydroxy group with the aid of hydrolysis, with analpha-halogeno-propionic acid ester.

28. The method of producing acids 0! the dimethyl cyclopentano polyhydrophenanthrene 10,13-dimethyl cyclopentano polyhydro pbenan RCOOR' whereinoccupies one of the 3- and l'l-positions and the other, It indicatingthe radical CnH2n, n being a whole number, R is a member of the groupconsisting of H, alkali metals and hydrocarbon radicals, X is a memberof the group consisting of OHand radicals which can be replaced by OHwith the aid of hydrolysis, and Y is a member of the group consisting ofH and CH3; and

' (2) the degradation products of the aforementioned compounds whereinthe BCOOR' group is replaced by =CH.R.COOR'.

30. Alkyl esters of the acids defined in claim 20.

31. An alkyl ester of 3,17'-dihydroxy-androstenyl-17"-propionicacid.

HANS-GEORG ALLARDT. LOTHAR S'IRASSBERGER.

